ABSTRACT Macrophages play a critical role in inflammation, systemic metabolism, tissue repair, host defense to microbial infection, and tumor surveillance. Emerging evidence shows that pro-inflammatory macrophages rely on glycolysis and fatty acid synthesis for the expression of pro-inflammatory genes, while anti-inflammatory macrophages require oxidative phosphorylation and fatty acid oxidation for anti-inflammation gene expression, suggesting that distinct aspects of cell metabolism regulate macrophage activation and polarization. MicroRNAs (miRNAs) are a novel class of small noncoding RNA regulators that control gene expression. Many miRNAs are selectively expressed in immune cells, and have been implicated in immune responses in host defense and autoimmune disease. Recent findings indicate that miRNAs are involved in fundamental macrophage functions by regulating cell metabolism. However, it is not clear how miRNAs regulate cell metabolism for macrophage activation and inflammatory phenotype determination. Using a lentivirus-based miRNA library that can reduce the inconsistency that occurs during the miRNA profiling process, we selected miRNAs that regulate inflammatory responses in macrophages and that have not been identified as regulators of metabolism and macrophage activation. Our long-term goal is revealing the role of miRNAs for the functional association of miRNAs with macrophage metabolism and phenotype determination, and applying that understanding for the treatment of inflammatory disease. miR-22, one of the miRNA candidates from the screening process, regulates the expression of 4-1BBL, a member of the TNF superfamily, and glucose transporter 1 (Glut1) in glycolysis during macrophage activation. However, it is not clear how miR-22 regulates the expression of 4-1BBL and Glut1 in macrophage activation in inflammatory disease. To investigate this, we hypothesize that miR-22 regulates the expression of 4-1BBL and Glut1 for the regulation of sustained inflammation in macrophages, dysregulation of which contributes to the pathology of psoriasis. We will examine the mechanism of miR-22-dependent regulation of macrophage metabolism and phenotype determination by using biochemistry and molecular biology approaches such as analysis of the signaling pathways and measuring cell metabolism (Aim 1) and study the role of miR-22 in inflammatory diseases and its therapeutic potential using a mouse model of imiquimod-induced psoriasis-like skin inflammation to test whether miR-22 administration can alleviate the pathology of psoriasis (Aim 2). Understanding the importance of miRNA in the regulation of macrophage metabolism will elucidate novel regulatory mechanisms in macrophage activation and phenotype determination in the development of inflammatory diseases. Our exploration of a previously unattended function and control mechanism of miRNAs in the regulation of cell metabolism will provide new translational insights about innate immunity in inflammatory disease development and treatment.